Metyylifenidaatin synteesitiestä

[untryrgos]

Hei kaverit, haluan jakaa joitakin kokemuksia Ritalinista. pyydän anteeksi huonoa englantia ja vähemmän kokemusta. äskettäin syntetisoin onnistuneesti metyylifenidaattia Ritalin-haposta. se on helppo tapa.
Ensinnäkin toin 75 grammaa Ritalin-happoa Kiinasta, koska se on laillinen aine eikä kukaan huomaa sitä.
Sitten valmistin 500ml metanoli-hcl-liuosta käyttämällä yksinkertaista tapaa, vain läpäisin vetykloridia metanoliin, kunnes se on kylläinen.Älä käytä vesiliuosta, koska se vähentää saantoa tai reaktio ei tapahdu Tee ympäristö kuivaksi on tärkeää.Voit käyttää molekyylitason seulaa näiden kuivaamiseen.
Sekoitetaan nämä yhteen pullossa, jossa on refluksilauhdutin voimakkaalla sekoituksella.Lämmitys rm 40-45 celsiusastetta, koska korkeampi lämpötila antaa metanolin ja hcl reagoida ja lisätä vettä.Ritalin-happo liukenee vain osa, mutta älä huoli siitä. Reaktio tapahtuu ja liuottaa koko hapon.
Kahden päivän kuluttua reaktio.Suola ilmestyy.Laita rm ja suola lämpimään paikkaan haihtua kaikki liuotin.Kuivaa rm ja uudelleenkiteyttää käyttää vettä.Älä kuumenna metyylifenidaatti kuivaa sitä.
Sopivalla annoksella vaikutus on tasainen ja rauhallinen ehkä koska minulla on ADHD.

 

[HewHiSt]

Hei, miten löydän ritaliinihapon toimittajan Kiinassa?

 

[untryrgos]

Löysin Wuhanin yrityksen. muutama yritys voi valmistaa sitä. löydät ne sivustolta nimeltä Chemical Book. löydän myös, että he myyvät sitä Alibabassa, etsi vain cas19395-41-6 (α-fenyylipiperidiini-2-etikkahappo).

 

[HewHiSt]

Kiitos kaveri

 

[gulbulklan]

Are they provided you info that their product is dl-threo-rtalinic? Because I'm looking for a while and everytime i ask about stereoisomer they doesnt even know what that is. In addition, the price is quite high, $250-300 for 100 g with shipping, and when it is racemic (probably), so I have to separate the stereoisomers, it is not cost-effective.

 

[ChemistryHobby]

I plan to do as you have done.
To make the HCl gas, I plan to use 20% solution HCl plus CaCl2.
I cannot find a higher concentration of HLC.
My question is will the gas be dry enough?
I guess i will have to dry it again through a drying tube of CaCl2??
Do I really have to use my 20% solution to make another solution more concentrated by bubbling HCL gas through it?

All HCL generators I see online seem to need 35% or greater solution of HCL with CaCl2.



How do I know when the methanol is full saturated with HCL?
I can check a PH? so it change colour?

You use the molecular sieve to dry out the methanol before bubbling through the HCL or after, or even during?

Thanks,,

 

[GnarleyBarley]

If you look up a common synthesis of ritalinic acid, you will see it produces 20:80 ratio threo to erythro isomer. What do you believe the chance of the ritalinic acid from china is produced by that method? Because obviously ritalinic acid is not the cheapest and getting only 20% of threo (of which only 50% will be the good dextro isomer) will obviously be problematic.

Edit:
https://doi.org/10.1021/jm00142a021
It is the 4-hydroxy version but same starting material without the 4-hydroxy should still lead to the 20:80 ratio.

Again only problematic if the ritalinic acid china produces is produced by this method. If they use another method which produces 50:50 threo:erythro, then no problem.

Also just so you know. SOCL2 can be used with methanol, instead of anyhydrous HCL

 

[ChemistryHobby]

Thanks for pointing that out, I have done some checking and

Normal Ritalinic acid .... CAS 19395-41-6
Better is DL-threo-Ritalinic Acid ...CAS 54631-24-2
Best is D-threo-Ritalinic Acid ...CAS 129389-67-9

I see that the first is available to buy.. but the others look more difficult to source.

I am making an assumption that DL-threo-Ritalinic Acid is used to make DL-threo-Methylphenidate hydrochloride.
and D-threo-Ritalinic Acid is used to make D-threo-Methylphenidate Hydrochloride / dexmethylphenidate hydrochloride / Focalin

I don't know what type is the generic Methylphenidate hydrochloride (Ritalin) sold as.. I guess threo and erythro mix as pointed out above but I don't know the ratios.. The generic Methylphenidate hydrochloride worked very well for me..

I am desperate to make Methylphenidate hydrochloride, I managed to get about 200 X 10mg pills earlier this year and it made a huge difference to my life. It really was the last thing that confirmed to me that I have ADHD.
I am not in a country where I can get a prescription for these from the doc. Its very controlled there.

I would appreciate any help in confirming my info/comments above or giving me pointers. I have an engineering mindset. but its in mechanical and electronic engineering. Which means I am open to learn things quickly but there will be huge gaps in my knowledge with regard to Chemical engineering

As always thank you for your help..

 

[GnarleyBarley]

Ritalin is DL-Threo, Best you can do is ask them what isomer they are selling. Your second option is to do a full threo synthesis but that requires piperidine (something already posted that synth, but without showing how to make the first step (which requires piperidine). If you want piperidine you will have to get it from a piperidine precursor. All of this is most likely too complicated and your best bet is ritalinic acid. Or just make dextromethamphetamine.

option A
Ritalinic acid esterification
Option B
Full threo methylphenidate synthesis (too complicated for novice I think considering the watched precursor and fancy reagents (tsnhnh2)

Google scholar and sci-hub will be your friend here

This is from my zotero phenidate collection (For the patents (e.g. 1) just google that exact phrase + "phenidate" at the end to find the patent
I think the use of Thionyl chloride instead of anyhydrous HCL is mentioned in one of the patents,

1.
Lal AN, Singh C. (71) Applicant: ZCL CHEMICALS LTD., Mumbai.

2.
Axten JM, Krim L, Kung HF, Winkler JD. A Stereoselective Synthesis of dl-threo- Methylphenidate: Preparation and Biological Evaluation of Novel Analogues. J Org Chem. 1998;63(26):9628-9629. doi:10.1021/jo982214t

3.
Sadanandan S, Gupta DK. Changing stereoselectivity and regioselectivity in copper( i )-catalyzed 5- exo cyclization by chelation and rigidity in aminoalkyl radicals: synthesis towards diverse bioactive N-heterocycles. New J Chem. 2020;44(8):3350-3365. doi:10.1039/C9NJ05166J

4.
Imai N, Achiwa K. Highly regioselective synthesis of trisubstituted pyrrolidines by 1,3-cycloaddition. Chem Pharm Bull. 1987;35(7):2646-2655. doi:10.1248/cpb.35.2646

5.
Bar-Or D, Rao NKR. (54) METHYLPHENIDATE DERIVATIVES AND.

6.
Laschat S, Dickner T. Stereoselective Synthesis of Piperidines. Synthesis. 2000;2000(13):1781-1813. doi:10.1055/s-2000-8218

7.
Metzner H. Ueber Phenacetylmalonsäureester. Justus Liebigs Ann Chem. 1897;298(2-3):374-390. doi:10.1002/jlac.18972980211

8.
Froimowitz M, Gu Y, Dakin LA, et al. Slow-Onset, Long-Duration, Alkyl Analogues of Methylphenidate with Enhanced Selectivity for the Dopamine Transporter. J Med Chem. 2007;50(2):219-232. doi:10.1021/jm0608614

9.
Misra M, Shi Q, Ye X, et al. Quantitative structure–activity relationship studies of threo-methylphenidate analogs. Bioorganic & Medicinal Chemistry. 2010;18(20):7221-7238. doi:10.1016/j.bmc.2010.08.034

10.
Meltzer PC, Wang P, Blundell P, Madras BK. Synthesis and Evaluation of Dopamine and Serotonin Transporter Inhibition by Oxacyclic and Carbacyclic Analogues of Methylphenidate. J Med Chem. 2003;46(8):1538-1545. doi:10.1021/jm0205292

11.
Tazeenuddin MA, Aswar AS. Novel one pot synthesis of dexethylphenidate hydrochloride with chiral purity. J Indian Chem Soc. 2020;97.

12.
Prashad M, Har D, Repic O, Blacklock TJ, Giannousis P. Enzymatic resolution of (±)-threo-methylphenidate. Tetrahedron: Asymmetry. 1998;9(12):2133-2136. doi:10.1016/S0957-4166(98)00220-1

13.
Deutsch HM, Shi Q, Gruszecka-Kowalik E, Schweri MM. Synthesis and Pharmacology of Potential Cocaine Antagonists. 2. Structure−Activity Relationship Studies of Aromatic Ring-Substituted Methylphenidate Analogs. J Med Chem. 1996;39(6):1201-1209. doi:10.1021/jm950697c

14.
Patrick KS, Kilts CD, Breese GR. Synthesis and pharmacology of hydroxylated metabolites of methyl phenidate. J Med Chem. 1981;24(10):1237-1240. doi:10.1021/jm00142a021

15.
Patrick K, Kilts C, Breese G. Synthesis of deuterium‐labelled methylphenidate, p‐hydroxymethylphenidate, ritalinic acid and p‐hydroxyritalinic acid. Labelled Comp Radiopharmac. 1982;19(4):485-490. doi:10.1002/jlcr.2580190404

 

[ChemistryHobby]

thanks you for your reply. I really appreciate the time it took to put me on the correct path..
My first task is in sourcing... I'll see what is available for me to buy..

I will update everyone going forward..

 

[ChemistryHobby]

I think I have found a good source of ready made 4F-MPH 4-Fluoromethylphenidate CAS 1354631-33-6
This would fix my problem so I don't have to try to make methylphenidate myself any more.
The country I am in, is one of the countries who manufacture many of the products discussed in this forum.

The only problem I have now is I am dealing directly to a company that manufacturers these product and would like I buy 1kg of the stuff.
After a lot of discussion, they have given me an minimum order quantity of 100g. (pretty sure they are making to order)
This is still way too much for my personal use..

If I can find someone who is looking for 95g or more, I can get my 5g added to the order for myself.

Anyone looking for 95g or more of 4F-MPH? You can deal directly, I am not interested in being in the middle of this trade. All of the work I have done so far is just for my own personal consumption for my own ADHD issues.

they ship to USA and Europe at the moment, I don't know about other countries..

thanks in advance..

 

[lamename69]

Depending on how much they want for the 100 g, I might be willing to take 20 gs or even 50.

 

[Smileygirlz]

I would be willing to get 20 grams or more. Price?

 

[ChemistryHobby]

It looks like I will have to make methylphenidate myself.
I will have to get Ritalinic acid but D-threo-Ritalinic Acid would be the best type..
And I think I will not like the answer... but is there practical way to differentiate between the three below? I guess not by solution or melting temp or colour or smell or by ph solution. I guess its the same for all three.
Is there is a simple or practical way for me to know which acid I am buying??

Normal Ritalinic acid .... CAS 19395-41-6
Better is DL-threo-Ritalinic Acid ...CAS 54631-24-2
Best is D-threo-Ritalinic Acid ...CAS 129389-67-9

 

[SoldadoDeDrogas]

Am I understanding this correctly, there is an "A-Oil" for methylphenidate - "R-oil" ? You just salt it out and you got ritalin?
It or it's analogs are not illegal or watched in the USA? I prefer MPH much more than dex-amph, how come this isn't more popular?